EuropeanJournalof

Nuclear Medicine

Review article

Radionuclide therapy of the thyroid S.E.M. Clarke Department of Nuclear Medicine, Guy's Hospital, St. Thomas Street, London SE1 9RT, UK

Abstract. Radionuclide therapy has a proven place in

the management of patients with thyroid disease. Iodine131 therapy has been established as both successful and safe in treating patients with thyrotoxicosis and thyroid malignancy. Protocols for patient treatment are now standardised, although some variation in practice exists across Europe. There remains much confusion as to which patients should be selected for treatment with radio-iodine for thyrotoxicosis and what dose should be administered. A review of the literature reveals that many of the theoretical hazards of treatment with radioiodine have not been encountered despite many years of usage. New therapies for medullary thyroid cancer are now being evaluated and recent promising developments are discussed in detail.

Key words: Radionuclide therapy Thyroid disease Thyrotoxicosis - Thyroid cancer - Radio-iodine 131 Iodine-131 MIBG - Medullary thyroid cancer Eur 3 Nucl Med (1991) 18:984-991

Introduction Radionuclide therapy has been used in the management of thyroid disease for over 40 years (Williams et al. 1949). Although initially iodine-130 was used, it was only a few years before iodine 131 became the radionuclide of choice for the therapy of thyrotoxicosis (Varma et al. 1970). It was also in the 1940s that the first reports of successful treatment of metastases from thyroid cancer with 131I appeared (Coliez et al. 1951). Since then, much experience has been gained and many series reported confirming the role of 1311 in the management of patients both with hyperthyroidism and thyroid cancer.

Despite these years of experience controversies still persist in the use of iodine 131 for both thyrotoxicosis and thyroid cancer. In this review, the current role of 1311 will be examined and the controversies explored. In recent years, new radiopharmaceuticals have been developed for therapy. Iodine 131 metaiodobenzylguanidine, initially employed in the treatment of phaeochromocytoma (Wieland et al. 1980), has been used to treat patients with medullary thyroid cancer by a number of groups (Clarke et al. 1987; Hoefnagel et al. 1985; Troncone et al. 1988). Initial results with this new agent will be evaluated. Finally, some speculations will be made about possible developments in the therapy of thyroid disease.

Radiopharmaceuticals for therapy

Iodine-131 This isotope of iodine with a half-life of 8.02 days and a medium energy beta emission (Emax 0.61 MeV) has many advantages as a therapy radionuclide. Its physical half-life is long enough for uptake and organification by the follicular thyroid cell, and the medium energy beta particle with a mean path length of about 1 mm is adequate to destroy the follicular cell. Gamma radiation facilitates imaging, which permits the uptake and localisation of 131I to be assessed prior to therapy. In addition, the radionuclide is cheap and readily available, and its liquid form makes dispending and oral administration simple. There are several disadvantages of this agent, however. Whilst a small abundance of gamma radiation is useful in therapy radionuclides for imaging purposes, the high abundance, high-energy gamma radiation of 131I results in poor images and contributes significantly to the whole-body radiation burden of the patient under

© Springer-Verlag 1991

985 treatment without significantly increasing the radiation damage to the target tissue. This high-energy gamma radiation also adds to the radiation dose to staff and relatives, necessitating admission and isolation of patients undergoing radio-iodine therapy. As a halogen, a further risk is one of vapourisation and subsequent ingestion by staff dispensing the dose. With adequate facilities and careful techniques the radiation dose to staff is kept to a minimum, but regular checks of thyroid uptake and personal dose metres are essential in those workers regularly administering 13~I.

incidence of recurrence if adequate doses of 131I are used (Hardistry et al. 1990). The dose of 131I is administered orally, and the patient is allowed home if the dose is not greater than the statutory limit (UK 1100 MBq, 30 mCi limit). Careful monitoring of thyroid function tests in the early posttherapy period is essential to detect the sudden fall in the thyroxine level that occurs in a small percentage of patients. Early hypothyroidism occurs most commonly after large doses of radio-iodine, but all patients must be followed after 131I therapy since hypothyroidism is a long-term sequel in the majority of patients, particularly those with Graves' disease.

Iodine-131 metaiodobenzylguanidine Metaiodobenzylguanidine (mIBG) was developed in Ann Arbor, Michigan, as a guanethidine analogue (Wieland et al. 1980). Its uptake into the neuroectodermally derived adrenal medulla has prompted its use in other neuroectodermally derived turnouts including neuroblastomas, paragangliomas, carcinoids and medullary thyroid cancer (MTC). Although only 30%-40% of MTC take up 131I-mIBG (Clarke et al. 1987; Moll et al. 1987), significant uptake is observed at some tumour sites. Therapy with this agent has been attempted, with significant palliative responses observed and some reports of tumour regression. The main disadvantage of this agent is its cost per dose.

Radio-iodine therapy in benign disease Thyrotoxicosis Dietary iodine is an essential requirement for the synthesis of thyroid hormones by the iodination of tyrosine residues. When 131I is administered orally in patients with thyrotoxicosis, metabolic incorporation into the' follicular cells of the thyroid epithelium results in the intracellular delivery of beta radiation doses to the metabolically active follicular cells with their subsequent destruction.

Practical aspects. The protocol for the administration of therapy doses of ~3~I to patients with thyrotoxicosis has been well established over the years. Patients to be treated should be rendered euthyroid before treatment. This is achieved using carbimazole or propylthiouracil. Beta blockers may also be used to control the symptoms as necessary. In patients with toxic diffuse goitre (Graves' disease), a preliminary long course of anti-thyroid drugs (12-24 months) may be used, since approximately 50% of patients so treated will achieve a complete remission. In those patients with Graves' disease who relapse or those with toxic nodular goitre, 1311 therapy is, in my opinion, preferable to surgery because of its lower morbidity (Hennemann et al. 1986) and low

Liquid vs. Capsules. The dispensing of volatile 1311 liquid must be performed with care in a suitable dispensing cabinet to minimise the radiation dose to the dispenser and contamination of the atmosphere. The hazards to the individual dispenser are minimised by using 13aI capsules, which also significantly reduces the risk of contamination by spillage. The benefits in terms of radiation protection are offset by the significantly increased cost of capsules compared with liquid and a loss of flexibility in dosage at the time of treating the patient. Admission following 1311 therapy. While the current UK limits on radio-iodine dose permit the administration of doses of up to 1110 MBq (30 mCi) to an out-patient providing precautions are observed with regard to travel on public transport and working, social and domestic contacts, other European contries have taken a much stricter line. Holland, for example, requires the admission of all patients receiving doses in excess of 180 MBq (5 mCi). The inability to avoid contact with babies, young children or pregnant women in the week posttherapy is also an indication to admit toxic patients for a therapy dose of 1311. Post-therapy advice and consent. Patients receiving radioiodine should be warned that they constitute a potential radiation hazard, albeit small. They should be advised before treatment of the statutory requirements with regard to travel and the need to avoid prolonged close contact with babies, young children or pregnant mothers, Guidelines for patients should contain precise information about the length of time and closeness of contact that the patients may have with their families, and this issue recently has been addressed (Culver and Dworkin 1991). Patients will also need to be advised to take approximately 1 week off work. They should be warned about the hazards of food preparation. The need to use separate cutlery to avoid saliva contamination and the suggestion to sleep apart from their partner remains the subject of debate but are considered by some to be sensible precuations to keep radiation dose to family members to an absolute minimum. The requirement to obtain informed consent prior to treatment varies

986 Table 1. Factors affecting efficacyof radio-iodine dose 1. Functioning mass of gland 2. Uptake of radio-iodine 3. Clearance of radio-iodine 4. Radio-sensitivityof the gland

between countries in Europe. In the UK, written informed consent is now required before treatment.

Dosage to be used. Considerable time has been spent attempting to establish a formula for calculating a radioiodine dose that will render the patient euthyroid without the risk of subsequent relapse or hypothyroidism (Becker 1982; Hayes et al. 1990). Careful calculation of dosage for individual patients also prevents unnecessary radiation being administered. Factors that need to be considered when assessing the efficacy of a radio-iodine dose are included in Table 1. Whilst some of these factors can be estimated readily, others such as radio-sensitivity, at present cannot be determined and remain an unquantifiable element. Much of the literature has concentrated on accurate calculations of thyroid weight. In simple Graves' disease, the weight is directly proportional to the functioning mass, assuming uniform iodine distribution in the absence of cysts or solid cold nodules. In toxic nodular goitre, however, the presence of suppressed thyroid tissue and/or cystic areas means that the estimated weight of the gland bears an unreliable relationship to the functioning mass. Uptake of radio-iodine can be readily calculated using a tracer dose of 13~I before the therapy dose (Becket 1982; Hayes et al. 1990). Care must be taken to keep the tracer dose as low as possible to avoid transient radiation damage to the thyroid, resulting in reduced uptake of the therapy dose. Similarly, clearance rates of ~3aI from the gland can be estimated from a pre-therapy tracer study, but the reproducibility of these values has not been adequately confirmed, and exogenous factors such as drugs or diet may alter the clearance rate between the tracer study and administration of the therapy dose (Becker 1982). Given the difficulties in accurately estimating the required dose to render a patient euthyroid, it is not surprising that many workers have opted for a fixed dose regimen or variable dose regimen based on the size of the gland as determined by palpation. It is generally accepted that whatever method is used to determine the dose, long-term hypothyroidism is inevitable for patients with Graves' disease treated with 131I, and many long-term studies exist that demonstrate the instance of hypothyroidism to be between 7% and 25% in the first year followed by an annual increment of 2%-4% (Becker 1982; Hardisty et al. 1990; Kinser et al. 1989; Staffurth 1987). Low-dose treatment regimens have, as might be predicted, a lower instance of hypothyroidism in the first year (Ching et al. 1977), but the

long-term outcome shows a significant incidence of hypothyroidism at 15 years (35%-40%) compared with 50%-70% incidence using the high-dose regimen. Some authors have advocated that an ablative dose of 13aI should be used (Kendall-Taylor et al. 1984). This should have the major advantage of rendering the patient hypothyroid within 1 year of treatment, after which thyroxine therapy is commenced. Once estabilised on treatment, the patient may be discharged from long-term follow-up. The major disadvantages, however, are that a significant number of patients prove extremely resistant to ablation and require multiple high doses of 131I to achieve hypothyroidism. In the study of Kendall-Taylor et al., of 225 patients treated with ablative doses of 131I, 36% had not become hypothyroid by the end of the first year. A further disadvantage is that these patients become totally dependent on thyroxine and will still require monitoring to ensure that they comply with their long-term thyroxine replacement regimen. In the Kendall-Taylor et al. study, 2% of patients who required thyroxine post-ablation were subsequently found not to be taking their treatment, and a further 3% were recognised by their physicians to be non-compliant. However, this method of treatment has much to commend it and could be considered cost-effective for both the patient and hospital department. Hardisty et al. (1990) studied medical workload and costs using two large series of hyperthyroid patients treated with varying doses of radio-iodine and have shown that the total costs, including patient costs, are greater for these treated with the lowdose regimen than those with the high-dose regimen.

Graves' ophthalmopathy The effect of radio-iodine on Graves' ophthalmopathy has been studied by a number of workers (Catz and Tsao 1965; Hamilton et al. 1967). Catz and Tsao have demonstrated that an improvement in ophthalmopathy can be obtained with radio-iodine ablation of the thyroid, which is believed to be on the basis of destruction of the antigenic stimulus to antibody formation. Pequequat et al. (1967), however, using non-ablative doses of radio-iodine showed a varied response. Of the 57 patients with ophthalmopathy treated with radio-iodine, 40% improved, 35% were unchanged, and 25% were made worse. Jones et al. (1969) observed that whilst lid retraction improved following radio-iodine therapy in patients with Graves' ophthalmopathy, exophthalmos remained unchanged or deteriorated, and peri-orbital oedema following treatment was observed in 50% of patients.

Selection of patients for radio-iodine therapy Although there is little debate amongst thyroid physicians about the efficacy of radio-iodine treatment for

987 thyrotoxicosis, there is considerable debate concerning which patients should receive radio-iodine treatment. Many clinicians still reserve treatment for post-menopausal women and adult males. The rationale for restricting treatment to these groups is the potential hazard of thyroid malignancy or leukaemia in children and the possible induction of genetic abnormalities in the off-spring in women treated with 131I. Several large series have now been published demonstrating that there is no increased incidence of leukaemia or thyroid malignancy in children or adults treated with radio-iodine (Hoffman 1984; Holm 1984; Pochin 1960; Saenger et al. 1968). In addition, surgery appears more hazardous in children, with acute complications occurring in 16%-35% of children undergoing sub-total thyroidectomy and permanent complications occurring in up to 8% (Bacon and Laury 1965; Ching etal. 1977; Reeve et al. 1969). Data to assess the risk of genetic abnormality induction are limited (Hayek et al. 1970; Safa et al. 1975; Sarkar et al. 1976). No data have yet demonstrated an increased risk of genetic defects in children of women who have undergone radio-iodine therapy, and the calculated dose to the ovaries is less than 3 rads per 370 MBq (Robertson and Gorman 1976), which is similar to that received by patients having a barium enema, a study not reserved for women beyond child-bearing years. All current evidence would therefore confirm that no risk exists to hyperthyroid children or to the progeny of hyperthyroid women treated with radio-iodine and that this therapy need not be restricted to certain patient groups.

Hypothyroidism following radio-iodine therapy for thyrotoxicosis The most common side effect of radio-iodine therapy is hypothyroidism. In Graves' disease, hypothyroidism is an inevitable end result of therapy, and it is proposed that late onset hypothyroidism is related to the natural history of Graves' disease rather than the side effect of radio-iodine therapy (Becker 1982). There is a bimodal pattern of onset of hypothyroidism, with a large percentage of patients becoming hypothyroid in the first year. The rate of onset of hypothyroidism is proportional to the dose of radio-iodine used, with high rates of early hypothyroidism in those treated with large doses (Hardisty et al. 1990; Staffurth 1987). Subsequently, there is an annual increment of 2 % - 4 % per year. There is, therefore, a need for continual monitoring of patients following radio-iodine therapy until they become hypothyroid and are started on thyroxine. The cost implications of long-term follow-up have been discussed in a previous section. Patients that rapidly become hypothyroid after radioiodine may become extremely symptomatic, with severe muscle pains and depression in addition to the usual

clinical features. Several authors have attempted to predict which patients will become rapidly hypothyroid (Lee et al. 1985; Wilson et al. 1988). Wilson et al. monitored a number of parameters in patients receiving radio-iodine therapy including T3, T4, TSH, thyroid microsomal antibodies and thyroglobulin antibody levels and found that these had no predictive value. A sharp rise in TSH receptor antibody content did appear to have some use in predicting those patients who became rapidly hypothyroid. Pre-treatment with anti-thyroid drugs has been suggested by some to reduce the incidence of hypothyroidism (Crocks et al. 1960), but others have not confirmed this finding (Goolden and Fraser 1969). The incidence of hypothyroidism in patients with toxic nodular goitre treated with radio-iodine is lower than in patients with Graves' disease due to the sparing of suppressed thyroid tissue and the natural history of toxic nodular goitre (Cooke et al. 1985). These patients, therefore, tolerate much higher doses of radio-iodine. There is still, however, a progressive incidence of hypothyroidism with time, about 2% per year reported in some series (Kinser et al. 1989), suggesting that these patients still require regular long-term follow-up.

Non-toxic multinodular goitre Whilst the most common indication for therapy with radao-lodme in benign disease is thyrotoxicosis, it may also be used to treat patients with non-toxic multinodular goitre. Indications for radio-iodine therapy are a gradually enlarging gland which is unsightly and may, with time, cause pressure symptoms or a recurrent, multinodular goitre following surgery. Several studies of radio-iodine therapy in multinodular goitre have been recorded (Keiderling et al. 1964; Leeper and Shimaoka 1980) and confirm a reduction in the size of the goitre in the majority of patients treated. Hypothyroidism is a rare complication in this group, but again long-term follow-up is recommended. Patients who present with pressure symptoms or significant retrosternal extension should be treated with radio-iodine with extreme caution as symptoms may worsen acutely with therapy. Surgery is generally the treatment of choice in this group. IP

.

.

.

Radio-iodine therapy in malignant disease The use of radio-iodine in the treatment of malignant thyroid disease falls into two main categories: thyroid ablation and therapy of recurrent disease.

Thyroid ablation The use of radio-iodine to ablate residual thyroid tissue following total or near-total thyroidectomy is a subject

988 of persistent debate. Many workers argue the logic of destroying residual thyroid tissue to enable better subsequent visualisation of recurrent disease and also greater uptake of the administered therapy in a small volume during recurrent disease (Beierwaltes 1978; Mazaferri 1981). In addition, thyroglobulin levels are more easily interpreted when normal thyroid tissue has been destroyed (Schlumberger et al. 1981). For those that advocate thyroid ablation, the dose to be used is also debated. Some advocate a relatively low dose (1100MBq, 30 mCi), stressing the benefits of minimising the radiation dose to patient and to staff (De Groot and Reilly 1982). Others use much higher doses of up to 200 mCi and justify these larger doses on the basis of more efficient thyroid ablation (Sisson 1983). Results of comparative studies suggest an increased survival in patients over 40 years old treated with radio-iodine and surgery compared with patients of this age treated by surgery alone (Krishnamurthy and Blahd 1977). No significant difference in survival rate was achieved by adding radio-iodine to surgery in those under 40 (Varma et al. 1970). Tubiana suggested that patients with poor prognostic features such as age or vein invasion or patients with only moderately differentiated tumours should be treated with surgery and radio-iodine (Tubiana 1982). Arad et al. have recently explored the use of fractionated doses of radio-iodine for ablation using 30-50 mCi doses repeated at weekly intervals up to 111 mCi (Arad et al. 1990). They found the fractionated dose achieved ablation in 25% of patients with no side effects reported as compared with 80% of patients treated with a standard regimen. All patients should discontinue thyroxine 1 month prior to radio-iodine treatment and will require admission for treatment with standard precuations.

Differentiated thyroid cancer The histological diagnosis of thyroid cancer gives some indication as to whether 13~I can be used in subsequent treatment (Table 2). The majority of follicular carcinomas retain the ability to take up 131I but 131I uptake can only be induced in about half of papillary tumours (Mazzaferri 1987). Those papillary tumours that take up 131I frequently contain follicular elements, but even tumours that show a purely papillary pattern may exhibit 13tI uptake under adequate TSH stimulation. Both follicular and papillary carcinomas may de-differentiate with time and lose their ability to trap iodine whilst retaining the ability to secrete thyroglobulin. Medullary thyroid cancers, anaplastic tumours and lymphomas of the thyroid do not take up ~31I, which therefore has no role in the management of these tumours following successful ablation of residual normal thyroid tissue. After ablation of the thyroid with surgery and radioiodine, patients are maintained on TSH suppressive doses of thyroxine to prevent TSH-mediated tumour

Table 2. Ideal characteristics of a therapy radio-nuclide 1. Beta or electroncapture radiation emitter 2. Less than 10% emittedgammaradiation 3. High target-to-backgroundratios 4. No non-specificuptake 5. Cheap 6. Readilyavailable

growth. The diagnosis and treatment of recurrent disease with 131I depends on the discontinuation of thyroxine for 4 weeks before the diagnostic study is performed with ~31I to allow the TSH levels to rise. If recurrent disease is identified on the diagnostic scan, the patient is admitted for a therapy dose of 131I and doses ranging from 80 to 200 mCi are used although the usual dose is 50 mCi (5500 MBq). In addition to discontinuing thyroxine, a low iodine diet is also recommended by some groups to further enhance 131I uptake into tumour sites. The dose to the tumour focus is dependent on the uptake of 131I within the tumour and its size, and small foci such as pulmonary metastases may receive doses up to 30000 rads. The decision on dosage to be used may be made in various ways. Some centres advise an empirical singledose regime for all patients. This approach is defended on grounds of simplicity and efficacy. However, other centres use dosimetric methods to estimate the dose for individual patients based on blood and urine collections and whole-body counting after a tracer dose of 131I (Maxon et al. 1983). One approach utilises the so-called BEL dosimetry which calculates the beta dose to the blood from a tracer study. Doses are selected to give a maximum of 2 Gy (200 rads) to the blood with no more than 4.44 GBq (120 mCi) retained in the whole body at 48 h (Benua et al. 1962; Leeper and Shimaoka 1980). Doses up to 450 mCi (16.65 MBq) have been used with no permanent suppression of the bone marrow observed. Benua et al. have shown, however, that average values of radiation delivered to the blood are significantly less than predicted for measurements after tracer doses, which calls into question the whole value of complex, time-consuming dosimetry studies prior to treatment (Benua et al. 1962). The dose delivered to recurrent tumours can also be estimated retrospectively (Kosal et al. 1986). Using those retrospective studies it has been found that doses of 150-170 mCi delivered to the tumour doses ranging from 400 to 29 000 rads. Following therapy doses of radio-iodine, the patient may recommence thyroxine and be followed up regularly to ensure that TSH suppression is maintained. Repeat ~3~I diagnostic scans may be performed at intervals of 6-12 months and further therapy doses administered as necessary. When all residual disease has been destroyed, thyroglobulin measurements can be used to follow the patients, thus avoiding the unpleasant requirement to discontinue thyroxine. A rise in thyroglobulin level is

989 an indication of recurrence, and further diagnostic studies should then be performed to localise recurrence.

Side effects of radio-iodine treatment for carcinoma of the thyroid Sialadenitis is one of the most commonly reported side effects following 13~I therapy and although rarely prolonged may be a cause of some discomfort. Nausea is another frequent side effect, particularly when high doses are used, generally occurring on day 1 of therapy. High fluid intake should be encouraged to prevent radiation cystitis. In patients receiving high doses of radioiodine or those with widespread bone metastases, transient drops in peripheral blood counts may be observed, but significant bone marrow suppression is not a problem in the majority of patients treated. Possible long-term sequellae of ~31I therapy include leukaemia and cancer of the bladder. Most of the reported deaths from leukaemia have occurred a few years after therapy, and no causal link can be proved. However, in the reported deaths a common preceding feature was that of aggressive therapy with total doses exceeding 1 Ci and intervals of less than 6 months between treatments (Benua etal. 1962; Edmonds and Smith 1986). Cancer of the bladder has been seen in a number of patients 14-20 years after treatment and again, occurred in those who had received over 1 Ci of radioiodine (Edmonds and Smith 1986). In a large study of children treated with radio-iodine, the incidence of infertility, miscarriage, prematurity and offspring with major congenital abnormalities did not differ significantly from that of the general population (Sarkar et al. 1976). Diffuse pulmonary metastases that show marked uptake of t3~I should be treated with doses of 150 mCi or less, since higher doses may result in radiation fibrosis (Tubiana 1982).

Prognostic significance of tumour iodine 131 uptake It has been suggested by some workers that patients whose tumours take up ~31I enjoy a higher survival rate than those which do not. Tubiana (1982) studied the 15-year survival of patients with local recurrence, lung metastases or bone metastases: 50% of patients with local recurrences that took up iodine were alive compared with 30% of patients whose local recurrences failed to trap iodine. Also 46% of patients with lung metastases and ~3~I uptake were alive at 15 years, but there were no survivors at 15 years when the lung metastases showed no uptake. Patients with bone metastases had a poor prognosis generally, with only 10% surviving from the group that took up iodine compared with 0% of those whose tumours did not. Patients with bone metastases tend to be older, and many have less well differentiated tumours. Both these facts may contribute to

their generally poor prognosis. Nemec et al. confirmed the findings in patients with lung metastases. Some 85% of patients with pulmonary metastases survived 10 years if the tumours took up radio-iodine compared with 0% of those whose turnouts did not.

~3q-mlBG therapy for medullary thyroid cancer Following the success of Wieland et al. (1980) in imaging the adrenal medulla, many groups have studied the uptake of 131I-mIBG in other neuroectodermally derived turnouts (Hoefnagel et al. 1985; Moll et al. 1987). Unlike phaeochromocytomas and neuroblastomas in which the sensitivity of mIBG uptake is 80%-90% (Hoefnagel et al. 1985), only 30%-40% of medullary thyroid cancers take up ~31I-mIBG (Clarke et al. 1987; Moll et al. 1987). The successful use of ~31I-mIBG in the therapy of patients with malignant phaeochromocytoma and neuroblastoma has prompted several groups to use it in therapeutic doses for patients whose recurrent medullary thyroid carcinoma shows significant uptake on diagnostic studies. Reports of therapy in 7 patients exist in the literature at the present time, and a complete response has been reported in 2, partial response in 2, palliation in 2 and no change in 1 (Clarke et al. 1987; Hoefnagel et al. 1985; Troncone et al. 1988). Palliative responses included relief of bone pain from metastatic disease and relief of diarrhoea. All patients treated had widespread disease with large tumour volumes. Although results at present are extremely limited, that a dramatic response was observed in a few patients warrants further work with 131I-mIBG in this uncommon tumour.

Practical aspects. Initial reports of therapy utilised doses of 3700-5500 MBq (Clarke et al. 1987; Hoefnagel et al. 1985), but recently higher doses have been used following the experience with doses of up to 1 GBq in patients with neuroblastoma (Troncone etal. 1988). Some workers are exploring the possible benefits of dose fractionation. 131I-mIBG is administered as a slow intravenous infusion because of the potential hazard of vasoactive peptide being released during administration. Adequate shielding must be provided during administration, and several commercial companies have now developed shielded systems which enable the dose to be administered with minimal handling by staff, thus significantly reducing the finger dosage received and reducing the chances of contamination. Admission to a specially designated room is mandatory. Therapy is extremely well tolerated, and problems with marrow suppression have not been reported. Frequency in timing. Although current experience is limited, as symptomatic relief is reported between 4 and

990 12 weeks post-therapy it is suggested that doses should be repeated at 2-3-monthly intervals up to 6 times. The major problem with t31I-mIBG therapy at present is its cost, which has prevented the use of this agent for many patients.

Future developments It is difficult to conceive of a better therapy radionuclide than 1311 for the treatment of hyperthyroidism and differentiated follicular thyroid cancer since it fulfills most of the criteria outlined in Table 2. However, given the intracellular localisation of iodine within the thyroid follicular cell, the possibility of using iodine 123 with its electron capture radiation or astatine 201, an alpha emitter, warrants exploration. An area of development that remains is dosimetry, with increasingly sophisticated methods being used to determine more accurately the exact dose to be administered. Experience with 131I-mIBG in the treatment of M T C is still very limited. The mechanism of uptake here has not been clarified, and the histochemical features of the tumours that take up m I B G have yet to be elucidated. Once the histological features of mIBG-positive tumours have been identified and the uptake mechanisms more clearly understood, it is hoped that endocrine or pharmacological manipulation may increase m I B G uptake into the tumours. In those patients whose primary tumours take up mIBG, the use of 131mIBG as an adjuvant treatment following primary surgery has yet to be explored. The high cost of this agent, however, is seriously inhibiting its development as a therapeutic option. The high uptake of 99mTc-(v)DMSA in 80% of M T C has prompted the development of 186Rh-(v)DMSA, a beta-emitting radiopharmaceutical (Blower et al. 1990). Preliminary results confirm that the biodistribution o f this new agent is the same as that of 99mTc-(v)DMSA (Allen et al. 1990). It is expected that this new agent will be available for therapy in the near future. The place of radionuclide therapy in benign and malignant thyroid disease has been established for many years. The recent developments of new radiopharmaceuticals give hope that radionuclide therapy in thyroid cancer will both expand and flourish.

References Allen S, Blake GM, McKeeney DB, Lazarus CR, Blower P, Singh J, Page C, Clarke SEM (1990) 186Re-v-DMSA: dosimetry of a new radiopharmaceutical for therapy of medullary carcinoma of the thyroid. Nucl Med Commun 11 : 220-221 Arad E, Flannery K, Wilson G, O'Mara R (1990) Fractionated doses of radio-iodine for ablation of past surgical thyroid tissue remnants. Clin Nucl Med 16:676-677 Bacon GE, Laury GH (1965) Experience with surgical treatment of thyrotoxicosis in children. J Paediatr 67 : 1 5

Becker DR (1982) Radioactive iodine (131I) in the treatment of hyperthyroidism. In: Beckers C (ed) Thyroid diseases. Pergamon Press, Paris, pp 145-158 Beierwaltes WH (1978) The treatment of thyroid carcinoma with radioactive iodine. Semin Nucl Med 8 : 79-84 Benua RS, Cicale NR, Sonenberg M (1962) The relation of radioiodine dosimetry to results and complications in the treatment of metastatic thyroid cancer. Am J Roent Radiat Ther Nucl Med 87:171-182 Blower P, Singh J, Clarke S, Bisnnaden M, Went M (1990) Pentavalent rhenium 186 DMSA: a possible tumour therapy agent. J Nucl Med 31:768 Brinker H, Hansen H, Anderson AP (1973) Induction of leukaemia by lalI treatment of thyroid carcinoma. Br J Cancer 28:232237 Catz B, Tsao J (1965) Total 13tI thyroid ablation for pretibial myxoedema. Clin Res 13:130 Ching T, Warden MJ, Fefferman RA (1977) Thyroid surgery in children and teenagers. Arch Otolaryngol 103:544-546 Clarke SEM, Lazarus CR, Edwards S, Murby B, Clarke DG, Roden T, Fogelman I, Maisey MN (1987) Scintigraphy and treatment of MCT with 131I MIBG. J Nucl Med 28:1820 Coliez R, Tubiana M, Sung J (1951) Disparition des metastases pulmonaires d'un cancer thyroiden sous l'influence d' iode radioactif. J Radiol Electro1 32:396-398 Cooke S, Ratcliffe G, Fogelman I, Maisey MN (1985) Br Med J 2:1491 Crooks J, Buchanan W, Wayne EJ, Macdonald E (1960) Clinical effects of pre treatment with methylthiouracil as results of ~3~I therapy. BMJ 1:151-154 Culver CM, Dworkin HJ (1991) Radiation safety considerations for post-iodine-131 hyperthyroid therapy. J Nucl Med 1991 32:169-173 De Groot LJ, Reilly M (1982) Comparison of 30 and 50 mCi doses of la~I for thyroid ablation. Ann Intern Med 96:51 Edmonds C, Smith T (1986) The long term hazards of treatment of thyroid cancer with radioiodine. Br J Radiol 59:45-51 Goolden AW, Fraser TC (1969) The effect of pre treatment with carbimazole in patients with thyrotoxicosis subsequently treated with radioiodine. BMJ 11:443-444 Hamilton R, Mayberry W, McConahey W, Hanson K (1967) Ophthalmopathy of Graves' disease: a comparison between patients treated surgically and patients treated with radioiodine. Mayo Clin Proc 42:812-818 Hardisty CA, Jones SJ, Hedley AJ, Munro DS, Bewsher PD, Weir RD (1990) J R Coll Physicians 24:36-42 Hayek A, Chapman EM, Crawford JD (1970) Long term results of treatment of thyrotoxicosis in children and adolescents with radioactive iodine. N Engl J Med 283 : 949-953 Hayes AA, Akre CM, Gorman CA (1990) 13~Iodine treatment of Graves' disease using modified early ~31iodine uptake measurements in therapy dose calculations. J Nucl Med 31 : 519-522 Hennemann G, Krenning EP, Sankaranarayanan K (1986) Place of radioactive iodine in treatment of thyrotoxicosis. Lancet I: 1369-1372 Hoefnagel CA, Dekraker J, Marcuse HR, Voute PA (1985) Detection and treatment of neural crest tumours using 13~I MIBG. Eur J Nucl Med 11 :A73 Hoffman DA (1984) Late effects of ~3~I therapy in the United States. In: Boice JD, Fraumeni JR (eds) Progress in cancer research and therapy, radiation carcinogenesis, epidemiology and biological significance, vol 26. Raven, New York, pp 273280 Holm LE (1984) Malignant disease following ~3~I in Sweden. In:

991 Boice JD, Fraumeni JF (eds) Progress in cancer research and therapy, radiation carcinogenesis, epidemiology and biological significance, vol 26. Raven, New York, pp 263-271 Jones D, Munro D, Wilson G (1969) Observations on the cause of exophthalmos after 13zI therapy. Proc R Soc Med 62:1518 Keiderling W, Emrich D, Hanzwaldi C, Hoffman G (1964) Ergebnisse der Radiojod-Verkleinerungs Therapie euthryreoter Strumen. Dtsch Med Wochenschr 89:453-457 Kendall-Taylor P, Keir M, Ross WM (1984) Ablative radioiodine therapy for hyperthyroidism: long term follow up study. BMJ 289:361-363 Kinser JA, Roesler H, Furrer T, Grutter D, Zimmerman H (1989) Non-immunogenic hyperthyroidism: cumulative hyperthyroidism incidence after radioiodine and surgical treatment. J Nucl Med 30:1960-1965 Koral KF, Adler SF, Carey J, Beierwaltes W (1986) Iodine 131 treatment of thyroid cancer: absorbed dose calculated from post therapy scans. J Nucl Med 27:1207-1211 Krishnamurthy GT, Blahd WH (1977) Radioiodine 131I therapy in the management of thyroid cancer: a prospective study. Cancer 40:195-202 Lee GS, Sander MP, Patton JA, Brill AB (1985) Serial thyroid iodine content in hyperthyroid patients treated with radioiodine. Clin Nucl Med 11 : 115-118 Leeper RD, Shimaoka K (1980) Treatment of metastatic thyroid cancer. Clin Endocrinol Metab 9:383-404 Maxon HR, Thomas SR, Hertzberg VS (1983) Relation between effective radiation dose and outcome of radioiodine therapy for thyroid cancer. N Engl J Med 309:937-941 Mazaferri E (1981) Papillary and follicular thyroid cancer. Annu Rev Med 32:171 196 Mazzaferri E (1987) Papillary thyroid carcinoma: factors influencing progno sis and current therapy. Semin Oncol 14: 315-332 Moll L, McEwan AJ, Shapiro B, Sisson J, Gross MD, Lloyd DR, Beals E, Beierwaltes WH, Thompson NW (1987) 131I MIBG scintigraphy of neuroendocrine tumours other than phaeochromocytoma and neuroblastoma. J Nucl Med 28 : 979-988 Pequegnat E, Mayberry W, McConahey W, Wyse E (1967) Large doses of radioiodine in Graves' disease: effect on ophthalmopathy and long acting thyroid stimulator. Mayo Clin Proc 42: 802-811 Pochin E (1960) Leukaemia following radioiodine treatment of thyrotoxicosis. BMJ 2:1545-1550 Rali JE, Alpers JB, Lewellen G, Sonenberg M, Berman M, Rawson K (1957) Radiation pneumonitis and fibrosis - a complication

of radioiodine therapy of pulmonary metastases from cancer of the thyroid. J Clin Endocrinol Metab 17:1263-1267 Reeve TS, Hales IB, White B, Thomas ID, Hunt PS (1969) Thyroidectomy in the management of thyrotoxicosis in the adolescent. Surgery 65 : 694-699 Robertson JS, Gorman CA (1976) Gonadal radiation dose and its genetic significance in radiation therapy of hyperthyroidism. J Nucl Med 17:826-835 Saenger EL, Thoma GE, Tomkins GA (1968) Incidence of leukaemia following treatment of hyperthyroidism. JAMA 205:855862 Safa AN, Schumacher OP, Rodriquez-Antunez A (1975) Long term follow up results in children and adolescents treated with radioactive iodine for hyperthyroidism. N Engl J Med 292:167171 Sarkar SD, Beierwaltes WH, Gill SP, Contey BJ (1976) Subsequent fertility and birth histories of children and adolescents treated with 13~iodine for thyroid cancer. J Nucl Med 17:460-464 Schlumberger M, Fragu P, Parmentier C, Tubiana M (1981) Thyroglobulin assay in the follow up of patients with differentiated thyroid carcinoma: comparison of its value in patients with or without normal residual tissue. Acta EndocrinoI 98:215-221 Sisson JC (1983) Applying the radioactive eraser: 131I to ablate normal thyroid tissue in patients for whom thyroid cancer has been resected. J Nucl Med 24: 743-748 Staffurth JS (1987) Hypothyroidism following radioiodine treatment of thyrotoxicosis. J R Coll Physicians 21 : 55-57 Troncone L, Ruffini V, Martenaggi P, Bambace J (1988) Can 131I MIBG therapy be usefully integrated in the treatment of MTC ? Preliminary results. In: Schmidt HAE and Buraggi GL (eds) Trends and possibilities in nuclear medicine. Schaltaner, pp 630-633 Tubiana M (1982) Thyroid cancer. In: Beckers C (ed) Thyroid diseases. Pergamon, Paris, pp 187-227 Varma VM, Beierwaltes WH, Notal M, Nishiyama R, Copp JE (1970) Treatment of thyroid cancer. JAMA 214:1437-1442 Weiner SC (1956) Oak Ridge radioiodine I T M for hyperthyroidism tenth anniversary. JAMA 161:628 Wieland DM, Win JL, Brown LE (1980) Radiolabelled adrenergic neuroblocking agents: adrenomedullary imaging with ~31I MIBG. J Nucl Med 21 : 349-353 Williams RH, Tovery BT, Jaffe H (1949) Radiotherapies. Am J Med 7 : 702 Wilson R, McKillop JH, Black E, Jenkins C, Thomson JA (1988) Early prediction of hypothyroidism following t3~I treatment for Graves' disease. Eur J Nucl Med 14:180-183